PROJECT SUMMARY/ABSTRACT As a clinical psychologist, my long-term career goal is to establish an independent career in patient-oriented research (POR), which focuses on integrating genetic, neuroimaging, and pharmacological approaches to 1) evaluate medications that target neurobiological and behavioral mechanisms involved in the development and maintenance of alcohol use disorder (AUD) and 2) tailor treatment to the individual based on genetic variation. My prior training taught me skills in the conduct of human laboratory and neuroimaging studies. My graduate training focused primarily on individual differences contributing to alcohol use and behavioral risk-taking, alcohol administration studies, and neuroimaging. As a postdoctoral fellow, I extended this training to include neuropsychological assessments and additional neuroimaging techniques and examined neural features contributing to the initiation of alcohol use and development of AUD. However, to achieve my long-term career goal, it is essential that I address critical gaps in my knowledge and training. I was recently appointed as a Research Assistant Professor in the Department of Psychiatry at the University of Pennsylvania (UPenn), which allows me to formally pursue an independent career in POR. The K23 mechanism will enable me to focus at least 85% of my time and effort to develop a career as an independent clinical researcher. My training objectives will progress in a logical fashion to prepare me for the transition to becoming an independent clinical researcher. These include: 1) acquiring new knowledge in genetics and pharmacology and applying this knowledge to understanding the mechanisms of medications to treat AUD, and the role of genetic factors in moderating these effects; 2) conducting a research project that integrates neuroimaging, genetic, and pharmacological approaches to examine the effects of the histamine H3 receptor antagonist, bavisant (BAV), on heavy drinking and neural responses to alcohol-related cues, and whether genetic variation in the HRH3 gene moderates these effects; and 3) developing the skills necessary to communicate my research findings, grant writing to secure subsequent research funding, and to collaborate in an interdisciplinary environment. I will accomplish these training objectives through relevant coursework, guidance from my mentors, attendance at seminars and workshops, and applied hands-on research training. This multi-modal approach will enable me to acquire new knowledge in areas essential to my career goals (i.e., genetics, pharmacology), implement the proposed research plan, and build an independent research program with the goal of obtaining an R01 award prior to the end of the K23 period. The research project is an integrative study designed to examine the effects of the histamine H3 receptor antagonist, BAV, on heavy drinking and neural responses to alcohol-related cues, and to explore whether genetic variation moderates these effects. Recent data indicate that histamine H3 receptor antagonists reduce alcohol consumption [1, 2]. Although the mechanism underlying these effects has not been fully defined,presynaptic H3 receptors help to regulate the release of dopamine, acetylcholine, and norepinephrine [3] andpostsynaptic H3 receptors may alter the enhanced dopaminergic signaling induced by alcohol [4, 5]. As such,BAV could suppress mesocorticolimbic dopamine release, thereby decreasing the reinforcing effects of alcohol and devaluing the previously rewarding properties of alcohol-related cues over time. To advance our understanding of BAV's effects and the effort to personalize the pharmacotherapy of AUD, we will conduct an 8-week, parallel-groups, placebo-controlled study of BAV in 100 heavy drinkers with DSM-5 AUD. Of these 100 participants, 44 will be recruited to complete two neuroimaging scans sessions, one prior to randomization and one following 3 weeks of study medication (BAV or placebo). Using this integrative approach, I will examine the effects of BAV on heavy drinking and neural responses to alcohol-related cues, correlate neural responses with behavior (heavy drinking), and explore whether genetic variation moderates these effects. Thus, findings from the proposed study could improve our understanding of a potentially efficacious medication for the treatment of AUD and contribute substantially to personalized care. The environment at the Center for Studies of Addiction (CSA) at UPenn is uniquely positioned to support my training needs. I will be mentored by Henry Kranzler, M.D (CSA Director, primary mentor) and co-mentored by scientists in the areas of pharmacology, genetics, neuroscience, and biostatistics. Mentorship will be complemented by focused coursework and participation in seminars and workshops at UPenn. In addition, the CSA will provide the practical resources needed to conduct my research, including use of an extensive infrastructure for participant recruitment, medical screening, data management, and biostatistical support. Additional financial support provided through the CSA will enable me to have 85% protected time to conduct the proposed training and research. This comprehensive, interdisciplinary mentored approach will enhance my clinical research skills and my ability to compete successfully for R01 funding and thereby establish an independent program of research.